Synthesis of valproate, valerate, and 1-methyl-1, 4-dihydropyridyl-3-carbonyloxy ester derivatives of Hantzsch 1,4-dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents

Abstract

A group of 3‐(hydroxyalkyl) 5‐alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐aryl‐3,5‐pyridinedicarboxylates (11–15) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate (16–18), valerate (19, 20), and 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy (25, 26) derivatives. Alternatively, the valproate derivative 3‐(2‐n‐propylpentanoyloxymethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate (34) was prepared by the reaction of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate (30) with chloromethyl valproate (33). This class of lipophilic compounds possess partition coefficients (Kp) in the 149–452 range, relative to the reference drug nimodipine (Kp = 187). All compounds exhibited potent calcium channel antagonist (CCA) activity (IC50 = 10–7 to 10–10 M range), relative to the reference drug nimodipine (IC50 = 1.49 × 10–8 M). CCA structure–activity relationships showed the parent C‐3 2‐hydroxyethyl compounds were more potent than their valproate derivatives, but less active than their valerate derivatives. Compounds having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy chemical delivery system (CDS) were approximately equiactive to the parent C‐3 2‐hydroxyethyl compounds. Anticonvulsant activity was determined in the maximal electroshock (MES) and subcutaneous metrazol (scMet) screens. 3‐(2‐Hydroxyethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate (12) provided modest protection in the MES and scMet screens. In the C‐3 valproate [CO2(CH2)nO2CCH(n‐Pr)2] group of compounds, those possessing an ethylene spacer (n = 2) provided protection in the MES screen, whereas those having a propylene spacer (n = 3) or methylene spacer (n = 1) were inactive. Related C‐3 valerate esters [CO2(CH2)2O2C‐n‐Bu] also provided protection in the MES screen, whereas those having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy CDS moiety were inactive. Drug Dev. Res. 48:26–37, 1999. © 1999 Wiley‐Liss, Inc.

Ethyl 5-carboxy-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate

“…Comment 4-Aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters of the nefidipine type have become almost indispensable for the treatment of cardiovascular diseases since they first appeared on the market in 1975 (Yiu & Knaus, 1999;Goldmann & Stoltefuss, 1991). The title compound, (I) (Fig.…”

Durchführung von chemischen Reaktionen im Mikrowellenfeld

“…Ebenso ist die CH-acide Komponente in weiten Grenzen variierbar [58]. Während die Biginelli-Reaktion bisher auf aromatische und heteroaromatische Aldehyde beschränkt ist, können bei der Hantzsch-Reaktion auch aliphatische Aldehyde eingesetzt werden.…”

Methyl 5-[N-(2-methoxycarbonyl-1-methylvinyl)carbamoyl]-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate monohydrate

“…Comment 4-Aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters of the nefidipine type have become almost indispensable for the treatment of cardiovascular diseases since they first appeared on the market in 1975 (Yiu & Knaus, 1999;Goldmann & Stoltefuss, 1991). The title compound, (I), is a nefidipine analog.…”